Abstract 5242: NFĸB pathway activation is a key determinant of tamoxifen tolerance and recurrence in breast cancer

Abstract

Abstract Nearly 75% of breast tumors express estrogen receptor (ER) and will be treated with endocrine therapies, such as tamoxifen or aromatase inhibitors. Despite their proven success, it is estimated that up to 50% of tumors fail on endocrine therapy and recur as aggressive therapy-resistant tumors. Therefore, preventing recurrence remains a major clinical problem. One hypothesis is that recurrences are driven by cells that survive therapeutic intervention. This poorly understood population is referred to as minimal residual disease that consists of drug-tolerant cells capable of surviving by entering a state of negligible growth. In trying to model tamoxifen tolerance and minimal residual disease in vitro, we have utilized the clonogenic assay where ER+ breast cancer cells' clonal growth and survival in the presence of tamoxifen is examined. Tamoxifen-tolerant cells show activation of the pro-inflammatory NFĸB pathway measured by an NFĸB-reporter, elevated expression of bona-fide target genes, and enhanced nuclear localization of p65 and p50, two major transcription factors of the NFĸB pathway. Tamoxifen does not directly activate the NFĸB pathway, but rather cells with high NFĸB activity proliferate independently of tamoxifen despite retaining ER expression. Mechanistically, NFĸB-dependent ER phosphorylation at S305 residue may contribute to failure to respond to tamoxifen. More importantly blocking NFĸB with multiple NFĸB inhibitors is sufficient to eradicate this population of tamoxifen-tolerant cells, suggesting NFĸB is required and can be exploited for therapy. We find that dimethyl fumarate, an FDA-approved anti-inflammatory and immune-modulatory drug, which we have established as an effective NFĸB inhibitor in breast cancer cells, prevents recurrence modeled both in vitro and in vivo. Altogether this work shows a novel role for the NFĸB pathway in promoting a population of cells that are tamoxifen tolerant and capable of seeding recurrent breast cancer disease. Furthermore, therapeutic targeting by an NFĸB inhibitor such as dimethyl fumarate can be used to eradicate residual disease and prevent breast cancer recurrence. Citation Format: Irida Kastrati, Svitlana D. Brovkovych, Joshua D. Stender, Elaine T. Alarid, Jonna Frasor. NFĸB pathway activation is a key determinant of tamoxifen tolerance and recurrence in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5242.